Monoclonal antibodies (mAbs) are used with increasing success against many tumors but, for brain tumors, the blood-brain barrier (BBB) is a special concern. The BBB prevents antibody entry to the normal brain; however, its role in brain tumor therapy is more complex. The BBB is closest to normal at micro-tumor sites; its properties and importance change as the tumor grows. In this review, evolving insight into the role of the BBB is balanced against other factors that affect efficacy or interpretation when mAbs are used against brain tumor targets. As specific examples, glioblastoma multiforme (GBM), primary central nervous system lymphoma (PCNSL) and blood-borne metastases from breast cancer are discussed in the context of treatment, respectively, with the mAbs bevacizumab, rituximab, and trastuzumab, each of which is already widely used against tumor outside the brain. It is suggested that success against brain tumors will require getting past the BBB in two senses: physically, to better attack brain tumor targets and conceptually, to give equal attention to problems that are shared with other tumor sites.